Alzheimer's disease (AD) is the most common form of dementia (loss of memory) in the elderly. Currently used therapeutic agents for Alzheimer's disease have any action mechanism which allows to improve cholinergic neurotransmission in the central nerve system with a cholinesterase inhibitor or suppress excitotoxicity with a N-methyl-D-aspartate (NMDA) type glutamate receptor inhibitor, however, all of the agents only provide mild improvement of the related symptoms. A radical treatment method has been expected to develop which suppresses or ameliorates progression of neurodegeneration responsible for Alzheimer's disease.
Principal pathological damage of AD, which is found in brain, is caused by extracellular deposits of β amyloid protein in the forms of plaques and vascular clogs, and intracellular neurofibrillary tangle of τ protein which is clumped and hyper-phosphorylated. Recent evidences demonstrate that an increased level of β amyloid in brain appears in advance of pathological changes of τ protein and correlates with cognitive decline. Recent studies also suggest that β amyloid is ascribed as the etiology of AD and reveal that clumped β amyloid has toxicity to neurons in cell culture.
β amyloid protein is mainly composed of peptides in the length of 39 to 42 amino acids and is produced from a large protein precursor called as amyloid precursor protein (APP) through consecutive action of protease and β- and γ-secretases. Rare but early onset AD cases are attributed to genetic mutation of APP which causes overproduction of any one of total β amyloid protein and isoforms thereof. Individuals with Down's syndrome have an extra chromosome containing an APP-encoding gene and they have an increased level of β amyloid and inevitably develop AD with age.
Semaphorins are endogenous proteins identified as factors which allow to degenerate nerve growth cone and suppress axon elongation. Semaphorin genes are categorized into eight gene subfamilies and classes based on their structures and are previously known to have approximately 20 molecular species (Non-patent document 1). However, little is known about main functions of most semaphorin families. More frequently studied one is a subfamily gene cluster called as Class III and among them, most frequently studied one is semaphorin 3A (Sema 3A) (Non-patent documents 2 and 3). Sema 3A protein is known to induce degeneration of growth cones in cultured nerve cells and inhibit regeneration and elongation of nerves at a low level of 10 pM within a short time.
In recent years, one research has been reported that dendritic cells detect Sema 3A protein, subsequently enter a lymph channel and transfer into a lymph node, suggesting that Sema 3A protein is involved in autoimmune disease (See e.g. Non-patent document 4), and other research has revealed that signals mediated by Sema 3A protein and its receptor, plexin-A4, have an important role in the onset of sepsis (See e.g. Non-patent document 6), and from these findings, Sema 3A protein is also known to be deeply involved in formations of pathological conditions of immune and infectious diseases, etc. Additionally, another researches have been reported that Sema 3A protein is secreted by cancer cells and tissues and blocks a signal pathway of mitogen-activated protein kinase (MAP) to suppress activation of T cells, and that pancreatic cancer patients with high expression level of Sema 3A in the cancer tissue have poor outcome, revealing that Sema 3A protein is also involved in malignant alteration of cancer (See, e.g. Non-patent documents 5 and 7).
Disseminated intravascular coagulation (DIC) is a serious pathological condition in which coagulation significantly activates in a systemic and persistent manner along with deteriorated underlying disease. DIC is known that its main symptoms are episodes of bleeding and organ disordering and the occurrence of these clinical symptoms leads to extremely poor outcome. Examples of underlying diseases inductive of DIC include sepsis, acute leukemia, solid cancer, premature separation of normally implanted placenta, amniotic fluid embolism, trauma, burn injury, connective tissue disease, shock, aortic aneurysm, fulminant hepatitis, liver cirrhosis, acute pancreatitis, rhabdomyolysis, thrombosis, severe infectious disease, etc., however, a relationship of the diseases and Sema 3A is not clear.
Previously an antibody to Sema 3A protein has been also reported. For example, researches have been reported that Sema 3A protein activity inhibitor such as anti-Sema 3A antibody is effective for treatment of Alzheimer's disease and Parkinson's disease (See Patent document 1), and also effective for treatment of immune disease and inflammatory disease (See Patent document 2). However, when a disease involving Sema 3A protein is prevented and/or treated with anti-Sema 3A antibody, it is not known a structure of anti-Sema 3A antibody used in order to effectively achieve the high drug efficacy.
As described above, Sema 3A protein is known to be involved in various pathological conditions and a technique for measuring Sema 3A protein in a high accurate manner is essential to elucidate the pathological conditions and develop a therapeutic agent for the conditions.